The myc family of proto-oncogenes is linked with a remarkable number of human cancers and with up to 15% of all human cancer deaths, however the etiology of these cancers remains largely unknown. The general goal of this proposal is to elucidate the mechanism by which deregulation of myc genes leads to tumorigenesis. More specifically, the focus is on analyzing nervous system tumors associated with myc genes, such as medulloblastoma, retinoblastoma, and neuroblastoma. These tumors are devastating cancers that most often occur in children and the current treatments are themselves associated with a high degree of morbidity, providing a particularly compelling impetus to better understand and more effectively treat these cancers. In Aim 1, the normal functions of myc genes in the nervous system will be analyzed using mouse knockouts, based on the premise that understanding the normal functions of proto-oncogenes often provides critical clues as to how they cause cancer when in excess. The myc knockouts are conditionally targeted to neural progenitor cells, the cells of origin for many nervous system tumors. In Aim 2, using myc transgenic mice, where myc is overexpressed in neural progenitors as in tumors, the goal is to study a nervous system tumor model. One area of particular interest in both of these aims is the cerebellum, where N-myc is both critical for normal development, probably as a Sonic Hedgehog effector, and where it is implicated in the genesis of medulloblastoma. In Aim 3, the link between myc and global chromatin histone modifications will be addressed. Excess myc drives high levels of histone acetylation suggesting that global changes in chromatin modification could may be linked to Myc-induced tumorigenesis. Together these aims will cooperatively address the research goals of defining how myc genes function in neurogenesis and induce neural cancers.